Combined VEGF and PDGF inhibition for neovascular AMD: anti-angiogenic properties of axitinib on human endothelial cells and pericytes in vitro

Siedlecki, Jakob; Wertheimer, Christian; Wolf, Armin; Liegl, Raffael; Priglinger, Claudia; Priglinger, Siegfried; Eibl-Lindner, Kirsten

doi:10.1007/s00417-017-3595-z

Cited by 41 publications

(34 citation statements)

References 67 publications

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“…Studies using PDGF inhibitors (such as Fovista and Axitinib), alone or in combination with other therapies, uncovered outcomes that might be useful for guiding management of ocular neovascularization [ 14 , 15 ]. In vitro, Axitinib was shown to modulate VEGFR and PDGRF and inhibit endothelial cells angiogenesis [ 16 ]. However, recent reports found no benefits with adding Fovista and Rinucumab (an anti-PDGFRβ antibody) to anti-VEGF therapy in neovascular AMD, causing the scientific community to reassess the role of PDGF in ocular angiogenesis.…”

Section: Resultsmentioning

confidence: 99%

Retinal and choroidal angiogenesis: a review of new targets

et al. 2017

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Retinal and choroidal neovascularization are a major cause of significant visual impairment, worldwide. Understanding the various factors involved in the accompanying physiopathology is vital for development of novel treatments, and most important, for preserving patient vision. The intraocular use of anti-vascular endothelial growth factor therapeutics has improved management of the retinal and choroidal neovascularization but some patients do not respond, suggesting other vascular mediators may also contribute to ocular angiogenesis. Several recent studies examined possible new targets for future anti-angiogenic therapies. Potential targets of retinal and choroidal neovascularization therapy include members of the platelet-derived growth factor family, vascular endothelial growth factor sub-family, epidermal growth factor family, fibroblast growth factor family, transforming growth factor-β superfamily (TGF-β1, activins, follistatin and bone morphogenetic proteins), angiopoietin-like family, galectins family, integrin superfamily, as well as pigment epithelium derived factor, hepatocyte growth factor, angiopoietins, endothelins, hypoxia-inducible factors, insulin-like growth factors, cytokines, matrix metalloproteinases and their inhibitors and glycosylation proteins. This review highlights current antiangiogenic therapies under development, and discusses future retinal and choroidal pro- and anti-angiogenic targets as wells as the importance of developing of new drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s40942-017-0084-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Retinal and choroidal angiogenesis: a review of new targets

et al. 2017

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“…Recently, Nakano et al 31 found that type 1 CNV show significantly lower vessel junction densities than type 2 CNV on OCT-A, suggesting type 1 CNV to represent more mature vessels. Due to the associated pericyte coverage, mature type 1 CNV are less prone to degradation by VEGF inhibition 32 . In this context, it might be beneficial to adjust anti-VEGF dosing to prevent CNV type 1 into type 2 conversion, while the persistence of supportive type 1 CNV and their biomarker SRF might be tolerable.…”

Section: Discussionmentioning

confidence: 99%

Impact of Sub-Retinal Fluid on the Long-Term Incidence of Macular Atrophy in Neovascular Age-related Macular Degeneration under Treat & Extend Anti-Vascular Endothelial Growth Factor Inhibitors

Fischer

Schworm

Kreutzer

et al. 2020

Sci Rep

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Sub-retinal fluid (SRF) has been discussed as a protective factor against macular atrophy in eyes with neovascular age-related macular degeneration (nAMD).To gauge the impact of SRF on macular atrophy, a database of 310 nAMD eyes was screened for eyes manifesting an SRF-only phenotype under treat & extend anti-VEGF treatment, defined as nAMD expressing CNV exudation beyond the three monthly anti-VEGF loading doses by SRF only without any signs of exudative intra-retinal fluid (IRF) for ≥3 years. incidence of macular atrophy and treatment responses were evaluated on multimodal imaging, including optical coherence tomography (OCT), blue autofluorescence (BAF) and near-infrared (NIR) confocal scanning laser ophthalmoscopy and fluorescence and indocyanine green angiography (FAG/ ICGA). In total, 27 eyes (8.7%) of 26 patients with a mean follow-up of 4.2 ± 0.9 (3-5) years met the inclusion criteria. Mean age was 72 ± 6 (range: 61-86) years. The SRF only phenotype was seen from baseline in 14 eyes (52%), and in 13 eyes (48%) after a mean 1.0 ± 1.3 (1-3) injections. In years 1 to 5, mean 7.5, 5.9, 6.1, 6.1 and 7.0 anti-VEGF injections were given (p = 0.33). Cumulative macular atrophy incidence was 11.5% at year 1, 15.4% throughout years 2 to 4, and 22.4% at year 5. In conclusion, eyes manifesting activity by SRf only in treat & extend anti-VeGf regimen for nAMD seem to exhibit rather low rates of macular atrophy during long-term follow-up. SRf might be an indicator of a more benign form of nAMD. The introduction of anti-vascular endothelial growth factor (VEGF) therapy in neovascular age-related macular degeneration (nAMD) has improved visual acuity and quality of life for millions of patients worldwide 1. In the era of anti-VEGF, the long-term maintenance of visual acuity is now challenged less by fibrovascular, and more by atrophic scars 2. Incidence and growth of macular atrophy are strongly dependent on CNV activity and resulting anti-VEGF therapy 2. CNV activity and the need for retreatment are mostly defined by the presence of macular fluid, i.e. intra-retinal fluid (IRF), sub-retinal fluid (SRF), and, less prominently, sub-pigment epithelium fluid 3. While many studies have shown a robust association of IRF with worsening visual acuity and increasing rates of macular atrophy 4-6 , subretinal fluid presence has paradoxically been shown to correlate with better visual acuity as compared to a completely dry macula, especially if located sub-foveally 7,8. The reasons for the documented beneficial effects of sub-retinal fluid on visual acuity are largely unclear. The most common hypothesis concludes that SRF presence reduces the risk of vision-threatening macular atrophy 9. Therefore, new modified treat & extend regimen tolerating SRF are currently being investigated 10. However,

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“…PDGF-BB is the predominant isoform of the PDGF family expressed in the eye [ 28 ]. VEGF and PDGF have a synergic effect on vascular homeostasis [ 29 , 30 ]. In the second part of our study, we found that microglia stimulate VEGF-A and PDGF-BB expression in, and secretion from, RMECs, with an even stronger effect induced by activated microglia.…”

Section: Discussionmentioning

confidence: 99%

“…Angiogenesis, migration, and proliferation are the most representative indices of endothelial cell function. The angiogenic growth factors VEGF and PDGF can enhance endothelial angiogenesis, migration, and the proliferation [ 30 , 39 – 41 ]. We showed that microglia promoted tube formation, wound healing, and proliferation of co-cultured RMECs, and activated microglia significantly enhanced these effects, in accordance with increased VEGF and PDGF levels.…”

Section: Discussionmentioning

confidence: 99%

Microglia enhanced the angiogenesis, migration and proliferation of co-cultured RMECs

Ding

Zhang

et al. 2018

BMC Ophthalmol

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BackgroundAttention is increasingly being given to microglia-related inflammation in neovascular diseases, such as diabetic retinopathy and age-related macular disease. Evidence shows that activated microglia contribute to disruption of the blood–retinal barrier, however, the mechanism is unclear. In this study, we aimed to clarify whether and how microglia affect the function of retinal microvascular endothelial cells (RMECs).MethodsWe activated microglia by Lipopolysaccharides (LPS) stimulation. After co-culturing static or activated microglia with RMECs using the Transwell system, we evaluated the function of RMECs. Vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) levels in the supernatant from the lower chamber were evaluated by ELISA. Angiogenesis, migration, and proliferation of RMECs were assessed by tube formation, wound healing, and WST-1 assays. The expression levels of tight junction proteins (ZO-1 and occludin) and endothelial markers (CD31 and CD34) were examined by Western blot analysis.ResultsWe successfully established an LPS-activated microglia model and co-culture system of static or activated microglia with RMECs. In the co-culture system, we showed that microglia, especially activated microglia stimulated VEGF-A and PDGF-BB expression, enhanced angiogenesis, migration, proliferation, and permeability, and altered the phenotype of co-cultured RMECs.ConclusionsMicroglia, especially activated microglia, play important roles in angiogenesis and maintenance of vascular function hemostasis in the retinal microvasculature. The mechanism needs further investigation and clarification.

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Combined VEGF and PDGF inhibition for neovascular AMD: anti-angiogenic properties of axitinib on human endothelial cells and pericytes in vitro

Abstract: Axitinib inhibits angiogenesis in endothelial cells and pericytes via VEGFR and PDGFR modulation in vitro. Further studies are needed to elucidate whether axitinib may also improve therapy of CNV in AMD in vivo by interference with pericyte stabilization of pathological vessels.

Cited by 41 publications

References 67 publications

Retinal and choroidal angiogenesis: a review of new targets

Retinal and choroidal angiogenesis: a review of new targets

Impact of Sub-Retinal Fluid on the Long-Term Incidence of Macular Atrophy in Neovascular Age-related Macular Degeneration under Treat & Extend Anti-Vascular Endothelial Growth Factor Inhibitors

Microglia enhanced the angiogenesis, migration and proliferation of co-cultured RMECs

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